Molecules controlled by the human histocompatibility gene complex (MHC) play a central role in immune responsiveness. The HLA-D region of the MHC encodes several subsets of highly polymorphic molecules which function in antigen presentation and alloreactivity. The nature and extent of HLA-D region heterogeneity observed in a reference Caucasian population can be further expanded by the analysis of HLA-D region molecules in other population groups. American Blacks represent a valuable resource for study of HLA-D region molecules because of unique characteristics which are different from populations presently studied: 1) Presence of an unidentified HLA-D specificity associated with DR3; 2) Alteration of genes in linkage disequilibrium resulting in the unusual antigen combination DR3,DQ blank; and 3) high frequency of DRw6-related alleles. These unique characteristics provide a probe to investigate and expand our knowledge of the molecular basis of HLA-D region diversity. Specific topics which will be addressed are the following: 1) Variability of HLA-D region gene number and gene expression; 2) Identification of new and/or null HLA-D region alleles (D,DR,DQ); 3) Polymorphism of expressed DR and DQ molecules; and 4) Relationship of defined serologic, molecular, and functional heterogeneity to the biology of the immune response and to the evolution of polymorphism. HLAL-D region molecules will be characterized from this population using functional studies to generate T cell clones against T cell recognition determinants; DNA studies using Southern and Northern blotting to identify variability in restriction fragment polymorphism, gene number and expression; and protein chemistry to characterize new and/or variant HLA-D region molecules by gel electrophoresis, amino acid sequence analysis and peptide mapping. While current studies of HLA-D region molecules have outlined a wide range of diversity, expansion of these studies into another population will aid in understanding the intricate way in which the diversity of the immune response is generated and controlled.